t-cell mediated immunity regulation and termination of immune
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T-Cell Mediated Immunity
Regulation and termination of immune responses
Lecture Objectives
Students should know:
What molecules of T cells are involved in T cell activation?
Priming and effector phases of T cell responseAntigen presenting cellsImmature versus mature dendritic cellsCo-stimulation signal/CD28/AnergyWhat happens in T cells after TCR activation?Th1 cells/Cell-mediated immunityGranulomaTh2 cells/ Humoral ImmunityRegulatory (suppressor) T cellsFunctions of Th1/2 cell cytokines Naïve versus memory T cells?Memory and effector T cells?
T cells:
Development in thymus
Migration out of thymus into blood(Naïve T cells)
Priming phase: Antigen-dependent differentiation in lymphoid tissues(to become memory and effector T cells)
Effector phase: Migration to sites of infection and effector function
Human:
Fetal development
Birth
School
Job
Figure 6-1
Figure 6-2
Green: MHC class IIRed: Lysosomal protein
Naïve T cells enter secondary lymphoid tissues and encounter antigens presented on dendritic cell MHC
Infection at skin: Dendritic cells pick up antigen, undergo maturation, and migrate to 2o LT.
Microorganisms in the blood:Trapped in spleen.
Infection at mucosal surface:Collected in tonsils, Peyer’s patch, appendix and Bronchial-associated lymphoid tissues .
In lymph nodes, naïve T cells migrate from blood to LN through specialized blood vessels called HEV (high endothelial venules).
Figure 6-5
Naive and some memory T cells express L-selectin to adhere on HEV in lymph nodes.
Each leukocyte subset expresses unique sets of adhesion molecules and chemokine receptors.
Endothelial cells in different tissues express different counter-receptors.
Multi-step homing process into LT
Naïve T cells express L-selectin and a chemokine receptor CCR7.Endothelial cells express L-selectin receptors (GlyCAM-1 and CD34) and CCR7-activating chemokines SLC and ELC.
Rolling (L-selectin) chemokinefirm adhesiondiapedesis
Integrins
Fluorescently labeled T cells migrating into Peyer’s patches
Kim lab
Interactions between CD4 and MHC II-expressing antigen presenting cells:
(T cell left : APC right)
(i) LFA-1 : ICAM-1 (adhesion)(ii) CD2 : LFA-3 (adhesion)(iii) CD4 (Lck) : MHC II (co-activation with TCR)(iv) TCR/CD3 : MHC II/peptide (activation of T cell)(v) CD28 : B7-1/B7-2 (co-activation with TCR)
(h) End result : activation of transcription factors.
CORE
Interactions between CD8 and MHC I-expressing antigen presenting cells:
(T cell left : APC right)
(i) LFA-1 : ICAM-1 (adhesion)
(ii) CD2 : LFA-3 (adhesion)
(iii) CD8 (Lck) : MHC I (co-activation with TCR)
(iv) TCR/CD3 : MHC I / peptide (activation of T cell through PIP2/DAG, IP3 pathway)
(v) CD28 : B7-1/B7-2 (co-activation with TCR)
CORE
Interaction of T cells and APCInteraction between TCR and Ag/MHC alone is not strong enough to sustain the contact between T cells and APCIntegrins and their receptors on T and APC strengthen the interaction so that TCR and CD28 receptors on T cells can receive prolonged and stable signals.Signals through the integrins on T cells also enhance T cell activation.
TCR-Ag/MHC
TCR-Ag/MHC interaction signals for LFA-1 to bind more firmly to ICAM-1
This is to ensure stable and prolonged interaction between T cells and APC.
Co-stimulatory receptor: CD28 (or CTLA4):B7
For full activation, T cells require signals from both TCR and CD28.
TCR activation alone is not sufficient to activate T cells.
CD28 and CTLA4 are T cell receptors for B7 molecules on APC.
CD28 is expressed by all T cells
CTLA4 is expressed by activated T cells.
CTLA4:B7 interaction negatively regulate T cell activation, limiting T cell activation and proliferation.
CD28: AcceleratorCTLA4: Brake
Figure 6-10
Professional antigen presenting cells
They are dendritic cells, B cells and macrophages
They express high levels of MHC I and II molecules
They express co-stimulatory molecules (e.g. B7)
They are differently distributed in lymphoid tissues (LT).
Dendritic cells are particularly important for initiation of T cell activation in lymphoid tissues.
Only these cells express B7
Different features of the three types of APC
Macrophages are good at presenting extracellular bacteriaDCs present bacterial and viral antigensB cells can efficiently present soluble antigens
Figure 6-12
Bacterial products such as LPS and cell wall products, and cytokines such as TNF-a differentiate immature DCs to mature DCs. Mature DCs express CCR7 and migrate from sites of infection to LT.Immature DCs are better in phagocytosis but lack co-stimulatory activity.Mature DCs express higher levels of MHCs and B7. They are better in antigen presentation and T cell activation but lack the phagocytic ability.
DC maturation
Figure 6-16
T cell activation process
CD4 for adhesion to MHC II and signal transduction (lck)Phosphorylation cascade occurs at early stage of signal tranduction
Figure 6-17 part 1 of 2
Intracellular events during T cell activation
Memorize the process
Major events involved in T-cell activationEvent Example
Cell-cell interaction T cell-APCCTL-target cell
Receptor-ligand binding TCR-antigen/MHC
Transmembrane signal transduction Activation of Lck
Generation of second messengers 1,4,5-IP3 and DG
Second-messenger effects Ca2+ mobilizationProtein kinase C activation
Biochemical pathways Phosphatidylinositol pathwayRas pathway
Cellular events Secretion of cytolytic granules
Early gene activation c-Myc, c-Fos
Intermediate gene activation Lymphokines, lymphokine receptors, nutrient receptors
Late gene activation Genes involved in cell proliferationIL-2, IL-2R, VLA-2 etc
A consequence of T cell activation:Enhanced IL-2 production and induction of IL-
2Rexpressionfor T cell proliferation
Immuno-suppressive drugs such as cyclosporin A and FK506 block NFAT activation induced by TCR activation, thus blocking production of IL-2.
Therefore these drugs inhibit T cell proliferation and activation.
Function of IL-2
Figure 6-23
Activated T cell express memory/effector type molecules
TCR activation without CD28/B7 co-stimulation leads to T cell anergy (unresponsiveness)
B7 is expressed only by activated professional antigen presenting cellsTherefore, recognition of Ag presented by immature APC (which don’t express B7) can induce T cell anergy.
c. Functional subsets of CD4 cells based on cytokine profile.
(1) T naive cell = Low levels of IL-2, 4, 5, 6, 10, 13, TNF-alpha, IFN-γ (these may not be detectable; all activated T cells produce IL-2)
(2) TH1 = IFN-γ, IL-2(Type 1 cytokines promote cell mediated immunity)
(3) TH2 = IL- 2, 3, 4, 5, 9, 13 (Type 2 cytokines promote humoral immunity)
(4) TH17 = IL-17, 22 (promote cutaneous inflammation)
(5) Subset control: TH1 polarization is promoted by IL-12 and IFN-γ IL-4 &10 inhibit.
TH2 polarization is promoted by IL-4; IFN-γ inhibits
TH17 polarization is promoted by IL-1 and IL-23; IL-4 and IFN-γ inhibit
CORE
T cell differentiation to Th1 or Th2
IgE response for defense against parasites or allergic responses is mediated by Th2 cells
Cell-mediated Humoral/Ig response
Regulatory T cells: suppress the function of Th1/2 cells
T cells can differentiate to Th1, Th2 or other T cell subsets.Many people believe that only Th2 cells can induce humoral immune response, while Th1 cells induce only CMI. But this is an overly simplified text book style view.Actually Th1 and Th2 cells are required for different aspects of humoral immune response.
TCR activation by APC
Thymus
Th1
Th2
IL-4
IFN
-
Tnp(Nonpolarized T cells)
Anti-microbial
Anti-parasitic
Th1 and Th2 cells produce different cytokines
Th0 (IL4+IFN-+)
Effector T cell subsets
Tregs
TGF1IL10etc
FoxP3Target
Activation signal
No activation
IL4 makes Th2, while IL12 makes Th1 cells
Cytokine secretion and biological activities of TH1 and
TH2 Subsets
Type 1Type 1 Type 2Type 2
IFN-IFN-IL-4IL-4IL-5IL-5IL-13IL-13
Cell-mediatedCell-mediatedImmune Immune responseresponse(intracellular(intracellularOrganisms)Organisms)
Some humoral Some humoral responses that responses that promote promote opsonizationopsonization
Anti parasitic, Anti parasitic, and IgE and IgE responsesresponses
General humoral General humoral responseresponse
T cellT cell
Figure 6-34
Very useful information !
&spleen
12.Cell mediated immune (CMI) responses
a. Function:(1) Control intracellular pathogens, tumors (2) Mediate transplant rejection(3) Mediate Type IV hypersensitivity(4) Contribute to granuloma formation(5) Contribute to chronic inflammation
Th1 cells regulate CMI
CORE
12. CMIb. Predominant cells and mediators
(1) TH1 lymphocytes (activated by Ag, IL-12 and IFN release IL-2 and IFN- induce TC, NK, and macrophage activation
(2) CD8+ TC1 and TC2 (activated by Ag/MHC I [endogenous pathway] and TH1 cytokines) have cytokine profile similar to TH1 and TH2, respectively; both are cytotoxic via TNFβ, perforin, granzymes, and Fas-induced apoptosis
(3) NK cells (see above for activation, etc.) release IFN-which activates macrophages and stimulates TH1 activity; also release GM-CSF that stimulates PMNs; lyse targets predominantly via granule components (e.g. perforin)
(4) Macrophages: next page
CORE
Monocytes/macrophages [mononuclear phagocytes] (activated by IFN and TLR ligands [e.g. LPS] or other cytokines [e.g. GM-CSF, TNF) (a) Tissue types: Kupffer, alveolar, etc. (b) Surface markers: C3b receptor (CR-1), LFA-1, Fc receptor, MHC II
(c) Macrophages play a central role in CMI and inflammation: (i) Antigen presenting cell, important in killing bacteria and lysing tumor cells
(ii) effector/mediator of delayed type hypersensitivity (DTH, see Type IV hypersensitivity)(iii) release IL-12 & induces TH1 response(iv) release IL-10 & suppress immune responses(v) release IL-1, 6, TNF and , INF and (vi) release enzymes, coagulation factors, complement components, superoxide (etc.), leukotrienes, and prostaglandins
12 b (4) Macrophages
CORE
Mediators of Cell Mediated ImmunityTh1 cells: DCs present Ag to naïve T cells and activate them. IL-12 produced from dendritic cells induce polarization of T cells into Th1. Produce IFN-g which activates CD8 T, NK and macrophages
CD8 T cells: also called T cytotoxic T cells. Kill virus-infected or tumor cells by TNF-b, perforin, granzymes and FAS ligand.
NK cells: IL-2, IL-12 and IFN-g activate NK cells to make them more efficient killer cells.
Macrophages: They are also activated by Th1 cytokine IFN-. Activated macrophages are more efficient in killing of engulfed or intracellular pathogens. They produce IL-12, IL-10, IL-1, IL-6, TNF- and IFN-, and release inflammatory mediators (coagulation factors, complement components, superoxide, leukotrienes and prostaglandins).
CD8 T cells (also called cytotoxic T cells, Tc or CTL)
• Cytolytic activity of CTL is promoted by IL-2, IL-12 & IFN
• Activated CTLs lyse targets with TNF, degranulation (perforin, granzymes), and/or Fas-induced apoptosis.
Cytotoxic CD8 T cells detect infected cells through TCR/Ag recognition and kill them
CD8+ T cells need the CD28 signal from APC at priming stage to become effector CD8+ cells,
But effector CD8+ cells don’t need the CD28 signal (at the effector stage) to kill target cells (APOPTOTIC cell death).
TCR activation polarization of CD8+ T cell cytoskeleton release lytic granules to kill target cells
Cytotoxins of CD8+ cells:
GranzymeGranulolysinPerforins
FAS-ligand: activates FAS to induce apoptosis
12 c.Role of endothelium Inflamed enothelial cells express P- and E-selectin and recruit
effector cells that mediate CMI (i.e. phagocytosis and cell killing)
d. Detection of cell killing activity by CD8 T cells:Cytolytic assays (51Cr release assay)
51CrCD8 51CrCD8
released
Target cells
51Cr
1. Labeling 2. Co-culture 3. Lysis & release of 51Cr
CORE
Figure 6-33
Th1 cells activate macrophages, making them highly microbicidal
GranulomaAggregated infected macrophages surrounded by T cells
A sign of chronic microbial infection
Pathogens persist in macrophages for long time
Insufficient macrophage activation by Th1 cells
Typical in M. tuberculosis infection
It is a defense mechanism that limits the spread of pathogens
A compromised situation between pathogens and the immune system
IFN- promotes antigen presentation, Th1 cell development, production of opsonizing Ab and macrophage activation
Functions of Th2 cells
Figure 6-36
Th2 cells activate B cells through cytokines and CD40L for IgG and IgE response
IgE, IgG4
Th1/2 choice made by the immune system has profound effect on the outcome of some diseases
(e.g. Leprosy)
Tuberculoid Leprosy
Infection by Mycobacterium leprae.
Th1 cells produce IFN-Activation of Macrophages
Destruction of intracellular bacteria.
Milder damage.
Patients survive.
Lepromatous Leprosy
Infection by Mycobacterium leprae.
Th2 cells cannot activateMacrophages.
Unchecked proliferation of intracellular bacteria.
Gross destruction of tissues.
Fatal.
Figure 6-21
Th17 cellsAnother effector T cell subset
Induced from naïve CD4+ or CD8+ T cells
Induced by IL-1, IL-6, or IL-23
Produce IL-17 and IL-22;IL-17 induces expression of G-CSF and chemokines for inflammation with neutrophils; IL-22 induces anti-bacterial proteins.
Important for anti-bacterial and anti-fungal infcetion; and chronic autoimmune inflammation in skin, joints and CNS
IL-2, IL-4 and IFN- inhibit the generation of Th17 cells
e. Regulatory T cells (also called Tregs or FoxP3+ cells)
• Specialized T cells that suppress immune cells such as T cells (naïve, Th1 and Th2), B cells, dendritic cells, macrophages etc.
• FOXP3+ CD4+ CD25+T cells constitute a major subset of regulatory cells. • Express CD25 and CTLA4• Produce TGF-β, and/or IL-10 to suppress target cells.• Prevent autoimmune diseases
• Regulatory T cell deficiency due to mutations of FOXP3 causes immune dysregulation, polyendocrinopathy, enteropathy, X linked syndrome (called IPEX or XLAAD) autoimmune diseases in multiple organs
• FOXP3 is the master transcription factor for regulatory T cells
• Commonly called Tregs.
Regulatory T cells
Effector T cells
InfectionCancer
Hyper-responses orAutoimmune diseases
Balanced for health
Too much Too much
TGF-1IL-10
IL-4/5/13IFN-
13. Regulation and termination of immune responses
a. Regulation by the nature of the antigen (e.g. polysaccharidesIgM)
b. Regulation by individual history (and genetic background), antigen dose and route of administration(e.g. oral immunization tolerance)
c. Regulation by antigen presenting cell (1) Co-stimulatory signals (e.g. B7 ligands for CD28 or CTLA4;
Activated T cells express CTLA4 for downregulation of T cell activation)(2) Suppressive cytokines (e.g. IL-10 and TGF-beta)
d. Modulation by antibody Immune complexes, receptor cross-linking, and activation and suppressive Fc
receptors (e.g. Fc receptors of NK cells and B cells)
e. T cells (regulatory T cells and other cells)(1) Th1/2 and Tc1/2 subsets and cytokine control (e.g. IL4 versus IFN-g)(2) soluble forms of TCRs (?) and cytokine receptors(3) CD4+CD25+ regulatory T cells suppress immune responses(4) FAS/FASL-mediated lymphocyte apoptosis
(activated lymphocytes express FAS, susceptible to cell death)
CORE
13. Regulation and termination of immune responses
f. Neuroendocrine controls(1) hormonal controls (e.g. stress-induced immunosuppression
by glucocorticoids and catecholamines.
g. Tolerance(1) Central tolerance (positive and negative selection)(2) Peripheral tolerance (clonal deletion, apoptosis and anergy)
CORE
Brain
Hypothalamus
Pituitary
Adrenal gland
Immune cells (through specific receptors)(results: suppression of immune cells)
Testes/ovary
CortisolCorticosterone
testosterone, estradiol, progesterone
Corticotropin
LH/FSH
Neuroendocrine controls Negative regulation of the immune system by stress hormones and sex hormones
Stress pathway
Reproductive pathway
CNS and Liver
Activation of the immune system
TNF-/IL-1/IL6
fever, sleepiness, fatigue, loss of appetite decreased libido
Regulation of the CNS by inflammatory cytokines
StressCortisol
Infection
CNS regulates the immune system (IS): The central nervous system affects the immune system through the neuroendocrine humoral outflow via the pituitary, and through direct neuronal influences via the sympathetic, parasympathetic (cholinergic) and peptidergic/sensory innervation of peripheral tissues. Thus, circulating hormones or locally released neurotransmitters and neuropeptides regulate major immune functions such as antigen presentation, secretion of cytokines, chemokines and antibodies, selection of T helper (Th)1 or Th2 responses, lymphocyte activity, proliferation and traffic.
IS regulates CNS: Certain cytokines such as interleukin (IL)-1, IL-6 and tumor necrosis factor (TNF)-a , released during an immune response activate the central components of the stress system, alter neurotransmitter networks activity and, thus induce fever, sleepiness, fatigue, loss of appetite and decreased libido.
IS affects the liver: Cytokines activate the hepatic synthesis of acute phase proteins - changes referred to as 'sickness behavior' and 'acute-phase response', respectively.
Adapted from http://www.endotext.org/adrenal/adrenal28/adrenalframe28.htmBy Ilia J. Elenkov